Hypertension-induced renal fibrosis and spironolactone response vary by rat strain and mineralocorticoid receptor gene expression.
BACKGROUND
Aldosterone promotes renal fibrosis via the mineralocorticoid receptor (MR), thus contributing to hypertension-induced nephropathy. We investigated whether MR gene expression influences renal fibrosis and MR antagonist response in a two-kidney, one-clip hypertensive rat model.


METHODS
Brown Norway (BN), Lewis, and ACI rats were randomised to spironolactone 20 mg/kg/day or water by gavage, starting four weeks after left renal artery clipping. Blood pressure was measured bi-weekly by tail cuff. After eight weeks of treatment, right kidneys were removed and examined for fibrosis and gene expression. Rats of each strain undergoing no intervention served as controls.


RESULTS
Blood pressure increased similarly among strains after clipping and was unaffected by spironolactone. Hypertension caused the greatest renal fibrosis in BN rats (p < 0.001 by ANOVA compared to other strains). Real-time PCR analysis showed greater renal collagen type I and MR gene expression in untreated, hypertensive BN rats (both p < 0.05 compared to other strains). Spironolactone attenuated fibrosis, with similar fibrosis among strains of spironolactone-treated rats.


CONCLUSIONS
Hypertension-induced renal fibrosis was greatest in rats with the highest MR gene expression. Spironolactone abolished inter-strain differences in fibrosis. Our data suggest that MR genotype may influence aldosterone-induced renal damage, and consequently, renal response to aldosterone antagonism.
Cavallari
Larisa H
LH
Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA. humma@uic.edu
Fashingbauer
Lucy A
LA
Camp
Joseph R
JR
King
Stephen T
ST
Geenen
David L
DL
D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects*; D006909:Hydroxyproline / Q000378:metabolism; D006973:Hypertension / Q000150:complications* / Q000235:genetics*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D018161:Receptors, Mineralocorticoid / Q000235:genetics* / Q000378:metabolism; D013148:Spironolactone / Q000008:administration & dosage / Q000494:pharmacology*; D013599:Systole / Q000187:drug effects
D024042:Collagen Type I; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone; D006909:Hydroxyproline